About 5-10% of breast cancer cases are hereditary and attributable to mutations in several susceptibility genes from which to date only 2 have been identified: BRCA1 (17q21) and BRCA2 (13q12). However, the BRCA genes only explain about 30% of familial breast/ovarian cancer, suggesting the existence of other susceptibility genes. 1 Familial cases not associated with mutations in the BRCA genes represent the best starting point for searching for these new genes using different approaches. One such approach is linkage study. Several loci on chromosomes 8p12, 10q23 and more recently 13q21 have been identified by linkage analysis, but the study of a large number of BRCA-negative families did not support the contribution of putative genes in these loci. [2][3][4] Another approach is focused on the study of genes involved in specific pathways. Given that BRCA1/2 are directly involved in DNA double-strand break repair (DSB) by homologous recombination (HR), several genes participating in the same pathway have been considered good candidates for breast cancer susceptibility. The HR reaction is catalyzed by RAD51, which interacts directly with BRCA2, and some related proteins, XRCC2, XRCC3, RAD51C and RAD51D, are also involved in the process. 5 Another protein, BACH1, a member of the DEAH helicase family, is known to interfere with DSB in a BRCA1-dependent manner. 6 Some of the genes encoding for these proteins have been analyzed for putative mutations involved in breast cancer susceptibility. Thus, BACH1 has been suggested as a candidate high-penetrance gene because 2 germline missense mutations were found in a study of 65 individuals who were BRCA1-negative; 6 however, 197 families without BRCA1/2 mutations were recently analyzed for mutations in BACH1, and none were found. 7 CHEK2 is another protein involved in DNA damage signaling that was recently identified as a candidate by linkage analysis; a specific variant of CHEK2 could be acting as a low-susceptibility allele in about 4% of familial cases not associated with BRCA. 8 In our study, we selected the XRCC2 gene as a new candidate for high penetrance because it is a parologue of RAD51 and because it was recently noted that the variant R118H in exon 3 of this gene increases sporadic breast cancer risk. 9 To test the possible involvement of XRCC2 in hereditary breast cancer, we selected as index cases 105 high-risk breast/ovarian cancer families that were not associated with either BRCA1 or BRCA2. The families came from the Spanish National Cancer Center (CNIO) and the Hospital Clı ´nico San Carlos in Madrid and were selected by choosing at least 3 women affected with breast and/or ovarian cancer (1 of them diagnosed before 50 years of age). All the women had given informed consent to participate in the study. The 105 index cases had an average age at diagnosis of 50.6 years, and 7 of these families had breast-ovarian cancer. Peripheral blood (PB) samples of the index cases were analyzed by single-stranded conformational polymorphism (SSCP) and denaturing gradient gel electrophoresis (DGGE) for mutations in the BRCA1/2 genes; it was confirmed that they did not carry mutations in the BRCA1/2 genes. 10,11 Two hundred PB samples from the National Blood Transfusion Center were selected as a control population; they were paired with the cases by sex and age.